REGULATION OF LYMPHOCYTE METABOLISM AND HOMEOSTATIS BY THE C-MYC/AP4 AXIS

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 DESCRIPTION (provided by applicant): Immune responses to pathogens require lymphocytes to orchestrate two temporally distinct phases of their activation. Upon antigen (Ag) encounter, B and T cells initiate activation, a program involving dynamic increases in gene expression, protein synthesis, and carbohydrate metabolism. Following the initiation phase, activation programs must be maintained to complete clonal expansion and generate the numbers of Ag- specific lymphocytes required for efficient pathogen clearance. The transcription factor cMyc plays an essential role in the initiation phase of lymphocyte activation. However, our data show that cMyc expression does not persist during the entire period of T cell responses. This result suggests that other transcription factors may substitute the loss of cMyc expression to maintain lymphocyte proliferation. We discovered that a cMyc- inducible transcription factor, AP4, is a critical cell-intrinsic regulator of CD8 T lymphocyte proliferation during the post-Myc phase. AP4 is required for continued transcription of many cMyc target genes via its direct binding to presumed regulatory elements and essential for protective immunity by CD8 T cells against viral infection. In this grant, we will study the biological significance of the temporally regulated requirements of the two transcription factors in immune responses that may balance normal lymphocyte proliferation and prevention of lymphomagenesis.